Our long-term objective is to determine the axonal factors involved in the failure to remyelinate in diseases such as multiple sclerosis (MS). In the studies proposed here, we will isolate and characterize axonal factors that control the migration, proliferation, and survival of oligodendrocyte precursor cells (OPC cells). We focus on the initial stages of developmental myelination to gain an understanding of the molecular functions and factors that lead to normal development of a myelin sheath. Then we will investigate those same functions and factors in MS brains to determine which factors are inappropriately expressed. We hypothesize that imbalances of axonal-related growth factors contribute to the failure of remyelination in MS.
In Specific Aim 1 we will characterize a process by which axonal molecules are released from a membrane fraction enriched in axonal plasma membrane. We will use medium that has been conditioned with OPC cells to stimulate the axonal-enriched fraction. Western blotting will be used to characterize the nature of the axonal factors (e.g., growth factors of different types) that are released from the axonal surface membrane. We will also characterize the types of receptors that have been activated.
In Specific Aim 2 we will investigate the influence of axonal factors and how axons regulate migration, proliferation, and survival of OPC cells. Preliminary studies found that solubilized factors can stimulate proliferation. Migration assays using both soluble and particulate fractions will allow us to determine whether axonal contact and/or soluble factors released from axonal membrane are responsible for initiation and cessation of migration and proliferation.
Specific Aim 3 directly tests the hypothesis that the axon-oligodendrocyte balance is altered in MS. Demyelinated areas from MS brain will be analyzed for growth factor composition (both type and ratio among them) in order to understand why oligodendrocytes migrate to the demyelinated region, proliferate, but do not remyelinate the demyelinated axons. We will obtain important information about the axonal molecules that control the early events of myelination (i.e. migration, proliferation, and survival of OPC cells), which eventually will enable researchers to pinpoint areas for therapeutic intervention. ? ?
|Bare, Dan J; Becker-Catania, Sara G; DeVries, George H (2011) Differential localization of neuregulin-1 type III in the central and peripheral nervous system. Brain Res 1369:10-20|
|Becker-Catania, Sara G; Nelson, Julie K; Olivares, Shantel et al. (2011) Oligodendrocyte progenitor cells proliferate and survive in an immature state following treatment with an axolemma-enriched fraction. ASN Neuro 3:e00053|